The current proposal focuses on the concept that thyroid hormone activation (T4 to T3 conversion) via the type 2 deiodinase (D2)plays a critical role in fuel homeostasis and energy expenditure. This concept originated from studies in brown adipose tissue (BAT), the main thermogenic tissue in human newborns and other small mammals. Recently, the discovery of D2 activity in human skeletal muscle has generated considerable excitement as it has become clear that deiodination is a common mechanism for metabolic control (1). Given this background, we were immediately intrigued by fact that BAT D2 is up-regulated in a mouse model of resistance to diet-induced obesity. In this model, supplementation with 0.5% bile acids prevents animals from becoming overweight or insulin-resistant when placed on a high fat diet. Intense collaborative investigation resulted in the first recognition of an FXR-independent metabolic pathway through which bile acids interact with the G-protein coupled receptor TGR5 and thus stimulate D2 in metabolically relevant tissues including BAT and human skeletal myocytes. Our preliminary studies indicate that other ; GPCRs also stimulate D2. These striking data suggest that the spectrum of metabolites controlling D2, and the range of target tissues in which this mechanism is operant may be even more extensive than previously thought. With this in mind, we have begun to search for novel D2-regulating substances, and have preliminary evidence supporting significant regulatory effects for xenobiotic compounds. Understanding how metabolic signals from rapidly fluctuating endogenous molecules and xenobiotic factors are integrated via the D2 pathway is the major goal of these studies. Ultimately, by understanding these novel mechanisms for thyroid-hormone dependent metabolic control, we hope to identify new targets and approaches for therapeutic intervention in metabolic disorders including type II diabetes, obesity, and the metabolic syndrome. PERFORMANCE SITE(S) (organization, city, state) Department of Medicine, Brigham and Women's Hospital, Boston MA PHS 398 (Rev. 09/04) Page 2 Form Page 2 Principal Investigator/Program Director (Last, First, Middle): BIANCO, ANTONIO C. KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project BIANCO, ANTONIO C. acb123 BWH PI DA SUVA, WAGNER S. BWH POST-DOC LARSEN, P. REED pr!123 BWH INVESTIGATOR OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells [X] No Q Yes If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://StemcellS.nih.qov/reqistrv/index.asp. Use continuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used. . Cell Line Disclosure Permission Statement. Applicable to SBIR/STTR Only. See SBIR/STTR instructions. d Yes C3 No PHS 398 (Rev. 09/04) Page 3 Form Page 2-contlnued Number the following pages consecutively throughout the application. Po not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, First, Middle): BIANCO, ANTONIO C. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description, Performance Sites, Key Personnel, Other Significant Contributors, and Human Embryonic Stem Cells 2-3 Table of Contents Detailed Budget for Initial Budget Period (or Modular Budget) Budget for Entire Proposed Period of Support (not applicable with Modular Budget) BudgetsPertainingtoConsortium/ContractualArrangements(notapplicablewithModularBudget) Biographical Sketch - Principal Investigator/Program Director (A/of to exceed four pages) 6-8 Other Biographical Sketches (Not to exceed four pages for each - Seeinstructions) 9-13 Resources 14 Research Plan 15-45 IntroductiontoRevisedApplication(Nottoexceed3pages;SBIR/STTRPhaseInottoexceed1page.). Introduction to Supplemental Application (Notto exceed one page) A. Specific Aims B. Background and Significance 16-17 C. Preliminary Studies/Progress Report/ ^_ (Items A-D: not to exceed 25 pages*) 17-22 Phase I Progress Report (SBIR/STTR Phase II ONLY) f * SBIR/STTR Phase I: Items A-D limited to 15pages. D. Research Design and Methods 22-38 E. Human Subjects Research 39 Protection of Human Subjects (Required if Item 4 on the Face Page is marked Yes) Data and Safety Monitoring Plan (Required if Item 4 on the Face Page is marked Yes and a Phase I, II, or III clinical trial is proposed) Inclusion of Women and Minorities (Required if Item 4 on the Face Page is marked Yes and is Clinical Research) Targeted/Planned Enrollment Table (for new and continuing clinical research studies) Inclusion of Children (Required if Item 4 on the Face Page is marked Yes) F. Vertebrate Animals 39 G. Literature Cited 39-44 H. Consortium/Contractual Arrangements I. Resource Sharing J. Letters of Support (e.g., Consultants) 45 Commercialization Plan (SBIR/STTR Phase II and Fast-Track ONLY) Checklist. 46 Appendix(Fivecollatedsets.NopagenumberingnecessaryforAppendix.) Checkif Appendix is Included Appendices NOT PERMITTED for Phase I SBIR/STTR unless specifically solicited Number of publications and manuscripts accepted for publication (notto exceed 10) 10 Other items (list): PHS 398 (Rev. 09/04) Page 4 Form Page 3